Project Abstract: Substantial biologic evidence indicates that mitochondria may play crucial role in development of skin cancer by their multiple functions in cellular progression. However, the importance of common variants and haplogroups in the mitochondrial genome in causing skin cancer is largely unknown. We propose to examine in detail the associations of genetic variants and haplogroups in the mitochondrial genome with the risks of melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) simultaneously in a nested case-control study within the Nurses Health Study (400 melanoma cases, 600 SCC cases, 600 BCC cases, and 1,670 matched controls). This innovative work will move this field forward by evaluating common variants using complementary approaches, i.e. to evaluate putative functional tag-SNPs that predict all coding-region variants in European mitochondrial genome to test for associations of common functional variants with skin cancer risk. We will also evaluate the associations between common haplogroups in European mitochondrial genome and skin cancer risk. Furthermore, we will assess the interactions between the common genetic variants and haplogroups in the mitochondrial genome and risk factors of skin cancer, such as constitutional host factors and UV exposure history, on skin cancer risk. This application will take advantage of the research opportunities nested within the existing well- characterized cohort, including cohort characteristics, quality of design, high follow-up rate, rigor in prospective host risk factor assessment, and high response rate of retrospective questionnaires. Our study will also take advantage of the previously confirmed cases of the three types of skin cancers, stored blood and DNA samples, and previously collected information on host risk factors and UV exposure history. This research will contribute to our understanding of the role of mitochondria in the etiology of skin cancer and provide the scientific basis to identify individuals at high-risk for skin cancer and to create individualized risk-management strategies. PUBLIC HEALTH RELEVANCE: Project Narrative: We propose a detailed evaluation of genetic variation in the mitochondrial genome in relation to the risks of melanoma, squamous cell carcinoma, and basal cell carcinoma simultaneously. This innovative work will move this field forward by systematically evaluating common variants using complementary approaches. This research will contribute to our understanding of the role of mitochondria in the etiology of skin cancer and provide the scientific basis to identify individuals at high-risk for skin cancer and to create individualized risk-management strategies.